We propose to continue our study of the intrinsic cardiac nerves (ICN). Previous work from our laboratory has established the chronotropic, dromotropic and inotropic capabilities of this system. We now plan to examine the role of the ICN in: 1) regulation of function in the denervated heart; 2) the mechanism of vagally-induced tachycardia; 3) the "vagotonic" action of digitalis; and 4) the cardiovascular responses to histamine. The study of these specific problems will also provide data on the ICN as a model ganglion cell/effector system with regard to the alterations of electrical and pharmacologic neural sensitivity following denervation. Dogs will be subjected to extrinsic surgical denervation of the heart to remove complicating adrenergic effects and to denervate the ICN. The responses of these animals will be compared to untreated controls and to animals pretreated with 6-hydroxydopamine. Inotropic effects will be evaluated using a four-chamber isovolumic heart preparation as well as isolated right and left atria. Chronotropic and dromotropic effects will be measured using direct electrical recording from the specialized conduction system, atria and ventricles. The long-term objectives are to more fully understand the function of the ICN as a regulatory system and the role which it plays in physiological and pharmacological responses of the heart. It is expected that the information so obtained will aid us in understanding the responses of the heart to ganglionic stimulants (e.g., nicotine). Additionally, we should learn more about the regulatory capabilities of the denervated (i.e., transplanted) heart and its pharmacologic vulnerability.